Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2).
Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2).
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DOI：
10.1371/journal.pone.0195278
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Eisenmann KM
中科院分区：
文献类型：
--
作者：
Dvorak KM;Pettee KM;Rubinic-Minotti K;Su R;Nestor-Kalinoski A;Eisenmann KM
肿瘤微环境（TME）促进肿瘤细胞的侵袭和转移。向癌前微环境转变的重要步骤是正常基质成纤维细胞转化为癌相关成纤维细胞（CAF）。CAF存在于大多数实体瘤中，并且可以通过细胞因子、趋化因子和生长因子分泌到TME中直接促进肿瘤细胞运动。TME对运动性肿瘤细胞中细胞骨架调节的确切作用仍然是个谜。保守的细胞骨架调节蛋白家族在无分支肌动蛋白丝的组装和/或成束中起着重要作用。哺乳动物透明蛋白相关蛋白2（mDia 2/DIAPH 3/Drf 3/Dia）组装动态F-肌动蛋白细胞骨架，其是肿瘤细胞迁移和侵袭的基础。因此，我们试图了解是否CAF衍生的趋化因子的影响乳腺肿瘤细胞的运动，通过修改福尔马林组装的F-肌动蛋白细胞骨架。在MDA-MB-231细胞中，相对于正常人乳腺成纤维细胞（HMF）-CM，来自WS 19 T CAF（一种人乳腺肿瘤相邻CAF系）的条件培养基（CM）显著且稳健地增加了伤口闭合和侵袭。相对于对照HMF-CM和WS 21 T CAF-CM，WS 19 T-CM还促进MDA-MB-231细胞中蛋白酶体介导的mDia 2降解，WS 21 T CAF-CM是一种乳腺CAF细胞系，其未能促进稳健的MDA-MB-231迁移。CM的细胞因子阵列分析鉴定了相对于对照WS 21 T CM，WS 19 T中上调的分泌因子。我们确定CXCL 12是影响mDia 2蛋白丢失同时增加MDA-MB-231细胞迁移的CM因子。我们的数据表明，CAFs促进肿瘤细胞迁移和侵袭的机制，通过CXCL 12分泌调节乳腺肿瘤细胞中的mDia 2-定向细胞骨架。
The tumor microenvironment (TME) promotes tumor cell invasion and metastasis. An important step in the shift to a pro-cancerous microenvironment is the transformation of normal stromal fibroblasts to carcinoma-associated fibroblasts (CAFs). CAFs are present in a majority of solid tumors and can directly promote tumor cell motility via cytokine, chemokine and growth factor secretion into the TME. The exact effects that the TME has upon cytoskeletal regulation in motile tumor cells remain enigmatic. The conserved formin family of cytoskeleton regulating proteins plays an essential role in the assembly and/or bundling of unbranched actin filaments. Mammalian Diaphanous-related formin 2 (mDia2/DIAPH3/Drf3/Dia) assembles a dynamic F-actin cytoskeleton that underlies tumor cell migration and invasion. We therefore sought to understand whether CAF-derived chemokines impact breast tumor cell motility through modification of the formin-assembled F-actin cytoskeleton. In MDA-MB-231 cells, conditioned media (CM) from WS19T CAFs, a human breast tumor-adjacent CAF line, significantly and robustly increased wound closure and invasion relative to normal human mammary fibroblast (HMF)-CM. WS19T-CM also promoted proteasome-mediated mDia2 degradation in MDA-MB-231 cells relative to control HMF-CM and WS21T CAF-CM, a breast CAF cell line that failed to promote robust MDA-MB-231 migration. Cytokine array analysis of CM identified up-regulated secreted factors in WS19T relative to control WS21T CM. We identified CXCL12 as a CM factor influencing loss of mDia2 protein while increasing MDA-MB-231 cell migration. Our data suggest a mechanism whereby CAFs promote tumor cell migration and invasion through CXCL12 secretion to regulate the mDia2-directed cytoskeleton in breast tumor cells.
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Formin MDIA2独立于其肌动蛋白成核活性稳定微管。
影响因子：
7.8
作者：
Bartolini, Francesca;Moseley, James B.;Schmoranzer, Jan;Cassimeris, Lynne;Goode, Bruce L.;Gundersen, Gregg G.
通讯作者：
Gundersen, Gregg G.
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
8
作者：
Burger, M;Glodek, A;Burger, JA
通讯作者：
Burger, JA
影响因子：
4.8
作者：
Eisenmann, Kathryn M.;West, Richard A.;Alberts, Arthur S.
通讯作者：
Alberts, Arthur S.
影响因子：
11.2
作者：
Di Vizio D;Kim J;Hager MH;Morello M;Yang W;Lafargue CJ;True LD;Rubin MA;Adam RM;Beroukhim R;Demichelis F;Freeman MR
通讯作者：
Freeman MR